diff --git a/changelog.d/10490.misc b/changelog.d/10490.misc
new file mode 100644
index 0000000000..630c31adae
--- /dev/null
+++ b/changelog.d/10490.misc
@@ -0,0 +1 @@
+Fix up type annotations to work with Twisted 21.7.
diff --git a/synapse/http/client.py b/synapse/http/client.py
index 2ac76b15c2..c2ea51ee16 100644
--- a/synapse/http/client.py
+++ b/synapse/http/client.py
@@ -847,7 +847,7 @@ class _ReadBodyWithMaxSizeProtocol(protocol.Protocol):
 
 def read_body_with_max_size(
     response: IResponse, stream: ByteWriteable, max_size: Optional[int]
-) -> defer.Deferred:
+) -> "defer.Deferred[int]":
     """
     Read a HTTP response body to a file-object. Optionally enforcing a maximum file size.
 
@@ -862,7 +862,7 @@ def read_body_with_max_size(
     Returns:
         A Deferred which resolves to the length of the read body.
     """
-    d = defer.Deferred()
+    d: "defer.Deferred[int]" = defer.Deferred()
 
     # If the Content-Length header gives a size larger than the maximum allowed
     # size, do not bother downloading the body.
diff --git a/synapse/replication/tcp/client.py b/synapse/replication/tcp/client.py
index e09b857814..3fd2811713 100644
--- a/synapse/replication/tcp/client.py
+++ b/synapse/replication/tcp/client.py
@@ -285,7 +285,7 @@ class ReplicationDataHandler:
 
         # Create a new deferred that times out after N seconds, as we don't want
         # to wedge here forever.
-        deferred = Deferred()
+        deferred: "Deferred[None]" = Deferred()
         deferred = timeout_deferred(
             deferred, _WAIT_FOR_REPLICATION_TIMEOUT_SECONDS, self._reactor
         )
diff --git a/synapse/util/async_helpers.py b/synapse/util/async_helpers.py
index 014db1355b..912cf85f89 100644
--- a/synapse/util/async_helpers.py
+++ b/synapse/util/async_helpers.py
@@ -49,6 +49,8 @@ from synapse.util import Clock, unwrapFirstError
 
 logger = logging.getLogger(__name__)
 
+_T = TypeVar("_T")
+
 
 class ObservableDeferred:
     """Wraps a deferred object so that we can add observer deferreds. These
@@ -121,7 +123,7 @@ class ObservableDeferred:
         effect the underlying deferred.
         """
         if not self._result:
-            d = defer.Deferred()
+            d: "defer.Deferred[Any]" = defer.Deferred()
 
             def remove(r):
                 self._observers.discard(d)
@@ -415,7 +417,7 @@ class ReadWriteLock:
         self.key_to_current_writer: Dict[str, defer.Deferred] = {}
 
     async def read(self, key: str) -> ContextManager:
-        new_defer = defer.Deferred()
+        new_defer: "defer.Deferred[None]" = defer.Deferred()
 
         curr_readers = self.key_to_current_readers.setdefault(key, set())
         curr_writer = self.key_to_current_writer.get(key, None)
@@ -438,7 +440,7 @@ class ReadWriteLock:
         return _ctx_manager()
 
     async def write(self, key: str) -> ContextManager:
-        new_defer = defer.Deferred()
+        new_defer: "defer.Deferred[None]" = defer.Deferred()
 
         curr_readers = self.key_to_current_readers.get(key, set())
         curr_writer = self.key_to_current_writer.get(key, None)
@@ -471,10 +473,8 @@ R = TypeVar("R")
 
 
 def timeout_deferred(
-    deferred: defer.Deferred,
-    timeout: float,
-    reactor: IReactorTime,
-) -> defer.Deferred:
+    deferred: "defer.Deferred[_T]", timeout: float, reactor: IReactorTime
+) -> "defer.Deferred[_T]":
     """The in built twisted `Deferred.addTimeout` fails to time out deferreds
     that have a canceller that throws exceptions. This method creates a new
     deferred that wraps and times out the given deferred, correctly handling
@@ -497,7 +497,7 @@ def timeout_deferred(
     Returns:
         A new Deferred, which will errback with defer.TimeoutError on timeout.
     """
-    new_d = defer.Deferred()
+    new_d: "defer.Deferred[_T]" = defer.Deferred()
 
     timed_out = [False]
 
diff --git a/synapse/util/caches/deferred_cache.py b/synapse/util/caches/deferred_cache.py
index 8c6fafc677..b6456392cd 100644
--- a/synapse/util/caches/deferred_cache.py
+++ b/synapse/util/caches/deferred_cache.py
@@ -16,7 +16,16 @@
 
 import enum
 import threading
-from typing import Callable, Generic, Iterable, MutableMapping, Optional, TypeVar, Union
+from typing import (
+    Callable,
+    Generic,
+    Iterable,
+    MutableMapping,
+    Optional,
+    TypeVar,
+    Union,
+    cast,
+)
 
 from prometheus_client import Gauge
 
@@ -166,7 +175,7 @@ class DeferredCache(Generic[KT, VT]):
     def set(
         self,
         key: KT,
-        value: defer.Deferred,
+        value: "defer.Deferred[VT]",
         callback: Optional[Callable[[], None]] = None,
     ) -> defer.Deferred:
         """Adds a new entry to the cache (or updates an existing one).
@@ -214,7 +223,7 @@ class DeferredCache(Generic[KT, VT]):
         if value.called:
             result = value.result
             if not isinstance(result, failure.Failure):
-                self.cache.set(key, result, callbacks)
+                self.cache.set(key, cast(VT, result), callbacks)
             return value
 
         # otherwise, we'll add an entry to the _pending_deferred_cache for now,
diff --git a/synapse/util/caches/descriptors.py b/synapse/util/caches/descriptors.py
index 1e8e6b1d01..1ca31e41ac 100644
--- a/synapse/util/caches/descriptors.py
+++ b/synapse/util/caches/descriptors.py
@@ -413,7 +413,7 @@ class DeferredCacheListDescriptor(_CacheDescriptorBase):
                 # relevant result for that key.
                 deferreds_map = {}
                 for arg in missing:
-                    deferred = defer.Deferred()
+                    deferred: "defer.Deferred[Any]" = defer.Deferred()
                     deferreds_map[arg] = deferred
                     key = arg_to_cache_key(arg)
                     cache.set(key, deferred, callback=invalidate_callback)